{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T17:46:21Z","timestamp":1775238381236,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,30]],"date-time":"2022-01-30T00:00:00Z","timestamp":1643500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002261","name":"Russian Foundation for Basic Research","doi-asserted-by":"publisher","award":["21-54-54005"],"award-info":[{"award-number":["21-54-54005"]}],"id":[{"id":"10.13039\/501100002261","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Since the beginning of the HIV epidemic, lasting more than 30 years, the main goal of scientists was to develop effective methods for the prevention and treatment of HIV infection. Modern medicines have reduced the death rate from AIDS by 80%. However, they still have side effects and are very expensive, dictating the need to search for new drugs. Earlier, it was shown that phospholipases A2 (PLA2s) from bee and snake venoms block HIV replication, the effect being independent on catalytic PLA2 activity. However, the antiviral activity of human PLA2s against Lentiviruses depended on catalytic function and was mediated through the destruction of the viral membrane. To clarify the role of phospholipolytic activity in antiviral effects, we analyzed the anti-HIV activity of several snake PLA2s and found that the mechanisms of their antiviral activity were similar to that of mammalian PLA2. Our results indicate that snake PLA2s are capable of inhibiting syncytium formation between chronically HIV-infected cells and healthy CD4-positive cells and block HIV binding to cells. However, only dimeric PLA2s had pronounced virucidal and anti-HIV activity, which depended on their catalytic activity. The ability of snake PLA2s to inactivate the virus may provide an additional barrier to HIV infection. Thus, snake PLA2s might be considered as candidates for lead molecules in anti-HIV drug development.<\/jats:p>","DOI":"10.3390\/ijms23031610","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T01:46:08Z","timestamp":1643593568000},"page":"1610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Anti-HIV Activity of Snake Venom Phospholipase A2s: Updates for New Enzymes and Different Virus Strains"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7576-2059","authenticated-orcid":false,"given":"Andrei","family":"Siniavin","sequence":"first","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Grinkina","sequence":"additional","affiliation":[{"name":"N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexey","family":"Osipov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladislav","family":"Starkov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7980-6191","authenticated-orcid":false,"given":"Victor","family":"Tsetlin","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4609-970X","authenticated-orcid":false,"given":"Yuri","family":"Utkin","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"A006841","DOI":"10.1101\/cshperspect.a006841","article-title":"Origins of HIV and the AIDS pandemic","volume":"1","author":"Sharp","year":"2011","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1517\/14712598.2010.496776","article-title":"Mucosal HIV transmission and vaccination strategies through oral compared with vaginal and rectal routes","volume":"10","author":"Yu","year":"2010","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a006866","DOI":"10.1101\/cshperspect.a006866","article-title":"HIV: Cell binding and entry","volume":"2","author":"Wilen","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/34571","article-title":"A new classification for HIV-1","volume":"391","author":"Berger","year":"1998","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7552","DOI":"10.1073\/pnas.0802203105","article-title":"Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection","volume":"105","author":"Keele","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S667","DOI":"10.1093\/infdis\/jiu369","article-title":"Origin of the transmitted virus in HIV infection: Infected cells versus cell-free virus","volume":"210","author":"Sagar","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7607","DOI":"10.1128\/JVI.00407-16","article-title":"Cell-Free versus Cell-to-Cell Infection by Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Type 1: Exploring the Link among Viral Source, Viral Trafficking, and Viral Replication","volume":"90","author":"Dutartre","year":"2016","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3389\/fimmu.2018.00260","article-title":"Mechanisms for Cell-to-Cell Transmission of HIV-1","volume":"9","author":"Bracq","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.jmb.2007.12.001","article-title":"Peptide mimic of the HIV envelope gp120-gp41 interface","volume":"376","author":"Kim","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.jmb.2011.04.042","article-title":"HIV-1 envelope glycoprotein biosynthesis, trafficking, and incorporation","volume":"410","author":"Checkley","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.chom.2017.06.012","article-title":"Fusion Stage of HIV-1 Entry Depends on Virus-Induced Cell Surface Exposure of Phosphatidylserine","volume":"22","author":"Zaitseva","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.virol.2014.02.004","article-title":"HIV-1 uncoating: Connection to nuclear entry and regulation by host proteins","volume":"454\u2013455","author":"Ambrose","year":"2014","journal-title":"Virology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a006890","DOI":"10.1101\/cshperspect.a006890","article-title":"HIV DNA integration","volume":"2","author":"Craigie","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1046\/j.1442-2026.2001.00174.x","article-title":"Venom as a source of useful biologically active molecules","volume":"13","author":"Bailey","year":"2001","journal-title":"Emerg. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.3390\/toxins5122533","article-title":"Secreted phospholipases A2 of snake venoms: Effects on the peripheral neuromuscular system with comments on the role of phospholipases A2 in disorders of the CNS and their uses in industry","volume":"5","author":"Harris","year":"2013","journal-title":"Toxins"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S237","DOI":"10.1194\/jlr.R800033-JLR200","article-title":"Phospholipase A2 structure\/function, mechanism, and signaling","volume":"50","author":"Burke","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6130","DOI":"10.1021\/cr200085w","article-title":"Phospholipase A2 enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention","volume":"111","author":"Dennis","year":"2011","journal-title":"Chem. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1172\/JCI40493","article-title":"Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice","volume":"120","author":"Sato","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13057","DOI":"10.1016\/S0021-9258(17)36794-7","article-title":"Diversity of group types, regulation, and function of phospholipase A2","volume":"269","author":"Dennis","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"899","DOI":"10.2174\/092986609788923365","article-title":"Structural and pharmacological features of phospholipases A2 from snake venoms","volume":"16","author":"Castro","year":"2009","journal-title":"Protein Pept. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.toxicon.2007.11.001","article-title":"Heterodimeric neurotoxic phospholipases A2--the first proteins from venom of recently established species Vipera nikolskii: Implication of venom composition in viper systematics","volume":"51","author":"Ramazanova","year":"2008","journal-title":"Toxicon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.bcp.2007.04.021","article-title":"Phospholipase A2 as targets for anti-cancer drugs","volume":"74","author":"Cummings","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e8055","DOI":"10.7717\/peerj.8055","article-title":"Phospholipase A2 from krait Bungarus fasciatus venom induces human cancer cell death in vitro","volume":"7","author":"Tran","year":"2019","journal-title":"PeerJ"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbalip.2007.12.001","article-title":"Antibacterial actions of secreted phospholipases A2. Review","volume":"1781","author":"Nevalainen","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15931","DOI":"10.1038\/s41598-017-16130-w","article-title":"Broad-spectrum antiviral agents: Secreted phospholipase A2 targets viral envelope lipid bilayers derived from the endoplasmic reticulum membrane","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Muller, V.D., Soares, R.O., dos Santos, N.N., Trabuco, A.C., Cintra, A.C., Figueiredo, L.T., Caliri, A., Sampaio, S.V., and Aquino, V.H. (2014). Phospholipase A2 isolated from the venom of Crotalus durissus terrificus inactivates dengue virus and other enveloped viruses by disrupting the viral envelope. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112351"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.biologicals.2019.12.002","article-title":"Potent virucidal activity against Flaviviridae of a group IIA phospholipase A2 isolated from the venom of Bothrops asper","volume":"63","author":"Brenes","year":"2020","journal-title":"Biologicals"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1172\/JCI6915","article-title":"Secreted phospholipases A(2), a new class of HIV inhibitors that block virus entry into host cells","volume":"104","author":"Fenard","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1128\/JVI.01790-06","article-title":"Lysis of human immunodeficiency virus type 1 by a specific secreted human phospholipase A2","volume":"81","author":"Kim","year":"2007","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1097\/COH.0000000000000534","article-title":"HIV subtype diversity worldwide","volume":"14","author":"Bbosa","year":"2019","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1172\/JCI131842","article-title":"PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients","volume":"130","author":"Pothlichet","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.jmb.2007.01.031","article-title":"An envelope-determined endocytic route of viral entry allows HIV-1 to escape from secreted phospholipase A2 entry blockade","volume":"367","author":"Maurin","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.toxicon.2011.05.021","article-title":"Crotoxin and phospholipases A2 from Crotalus durissus terrificus showed antiviral activity against dengue and yellow fever viruses","volume":"59","author":"Muller","year":"2012","journal-title":"Toxicon"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7777","DOI":"10.1007\/s00018-021-03985-6","article-title":"Snake venom phospholipase A2s exhibit strong virucidal activity against SARS-CoV-2 and inhibit the viral spike glycoprotein interaction with ACE2","volume":"78","author":"Siniavin","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.toxicon.2003.11.002","article-title":"Excitement ahead: Structure, function and mechanism of snake venom phospholipase A2 enzymes","volume":"42","author":"Kini","year":"2003","journal-title":"Toxicon"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1124\/mol.60.2.341","article-title":"A peptide derived from bee venom-secreted phospholipase A2 inhibits replication of T-cell tropic HIV-1 strains via interaction with the CXCR4 chemokine receptor","volume":"60","author":"Fenard","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S83","DOI":"10.1016\/j.jcv.2004.09.010","article-title":"Small animal model of HIV-1 infection","volume":"31","author":"Rytik","year":"2004","journal-title":"J. Clin. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1128\/jvi.68.3.1581-1585.1994","article-title":"A new subtype of human immunodeficiency virus type 1 (MVP-5180) from Cameroon","volume":"68","author":"Hauser","year":"1994","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"27403","DOI":"10.1038\/srep27403","article-title":"Identification of potent maturation inhibitors against HIV-1 clade C","volume":"6","author":"Timilsina","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.toxicon.2010.12.012","article-title":"cDNA cloning, structural, and functional analyses of venom phospholipases A2 and a Kunitz-type protease inhibitor from steppe viper Vipera ursinii renardi","volume":"57","author":"Tsai","year":"2011","journal-title":"Toxicon"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0003-2697(89)90022-5","article-title":"A sensitive and continuous fluorometric assay for phospholipase A2 using pyrene-labeled phospholipids in the presence of serum albumin","volume":"177","author":"Radvanyi","year":"1989","journal-title":"Anal. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e569","DOI":"10.7717\/peerj.569","article-title":"Role of enzymatic activity in muscle damage and cytotoxicity induced by Bothrops asper Asp49 phospholipase A2 myotoxins: Are there additional effector mechanisms involved?","volume":"2","author":"Angulo","year":"2014","journal-title":"PeerJ"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nprot.2007.517","article-title":"Tetrazolium-based colorimetric assay for the detection of HIV replication inhibitors: Revisited 20 years later","volume":"3","author":"Pannecouque","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/oxfordjournals.aje.a118408","article-title":"A simple method of estimating fifty per cent endpoins","volume":"27","author":"Reed","year":"1938","journal-title":"Am. J. Epidemiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1124\/mol.58.5.1100","article-title":"Polyanionic (i.e., polysulfonate) dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps (reverse transcriptase\/integrase) in the virus replicative cycle","volume":"58","author":"Witvrouw","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1089\/aid.2010.0177","article-title":"Construction and phenotypic characterization of HIV type 1 functional envelope clones of subtypes G and F","volume":"27","author":"Revilla","year":"2011","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1089\/aid.2018.0055","article-title":"HIV-1 Genetic Diversity in Recently Diagnosed Infections in Moscow: Predominance of AFSU, Frequent Branching in Clusters, and Circulation of the Iberian Subtype G Variant","volume":"34","author":"Karamov","year":"2018","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jviromet.2016.03.008","article-title":"Comparison of three quantification methods for the TZM-bl pseudovirus assay for screening of anti-HIV-1 agents","volume":"233","author":"Xing","year":"2016","journal-title":"J. Virol. Methods"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"W488","DOI":"10.1093\/nar\/gkaa216","article-title":"SynergyFinder 2.0: Visual analytics of multi-drug combination synergies","volume":"48","author":"Ianevski","year":"2020","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1610\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:11:31Z","timestamp":1760134291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,30]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031610"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031610","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,30]]}}}